Boston Professional Events List

Cancer Immunotherapy and Combinations

Date

Link to Website

Organizer

CHI Conferences

Venue

Westin Copley Place

Location

10,
Huntington Ave

Boston,

MA,

USA,

ZIP: 02116

Phone:

Cancer immunotherapy has ushered in a new era in the development of anti-cancer agents. The remarkable clinical response demonstrated by first-generation checkpoint antibodies has garnered significant interest by developers, quickly creating a broad and robust cancer immunotherapy development landscape. The discovery of new cancer immunotherapies continues to grow as developers find new ways to modulate the immune response beyond or in combination with checkpoint inhibition. These new approaches are poised to significantly enhance the potential of obtaining durable clinical effects in a wider range of cancers.

Who should attend: Executives, Directors, Managers, Researchers, and Scientists from pharma, biotechs, academia, government and healthcare organizations working in fields such as oncology, molecular biology, immunology, drug discovery, biologics, cancer immunotherapy.

Agenda

TUESDAY, JUNE 13

7:00 am Registration Open and Morning Coffee

TARGETING TREGS AS A NOVEL IMMUNOTHERAPY APPROACH

8:25 Chairperson’s Opening Remarks

Dario Vignali, Ph.D., Vice Chair and Professor of Immunology, University of Pittsburgh School of Medicine

8:35 Targeting Inhibitory Mechanisms in Cancer

Dario Vignali, Ph.D., Vice Chair and Professor of Immunology, University of Pittsburgh School of Medicine

The relative importance of different Treg suppressive mechanisms remains contentious. The signals that maintain Treg stability and potentiate their function remain obscure. The immune cell surface ligand semaphorin-4a (Sema4a) on conventional T cells and DCs, and the Treg-restricted receptor neuropilin-1 (Nrp1) interact to potentiate Treg function. Nrp1 ligation maintains Treg stability and function in highly inflammatory sites but is dispensable for the maintenance of immune homeostasis, highlighting Nrp1 as a potential immunotherapeutic target in cancer.

Here we report that selective Helios deficiency within CD4 Tregs leads to enhanced antitumor immunity through induction of an unstable phenotype and conversion of intratumoral Tregs into T effector cells within the tumor microenvironment. Induction of an unstable Treg phenotype is associated with enhanced production of proinflammatory cytokines by tumor-infiltrating but not systemic Tregs and significantly delayed tumor growth. Ab-dependent engagement of Treg surface receptors that result in Helios down-regulation also promotes conversion of intratumoral but not systemic Tregs into T effector cells and leads to enhanced antitumor immunity.

10:50 Development, Discovery and Details of the Oral Small Molecule Checkpoint Inhibitors, CA170 and CA327

David Tuck, M.D., CMO, Curis, Inc.

CA-170 is a first-in-class, orally-available, small molecule antagonist of the immune checkpoints PD-L1 and VISTA. CA-170 is currently undergoing investigation in a Phase I clinical trial in patients with advanced solid tumors and lymphoma. CA-327 is a first-in-class, orally-available, small molecule antagonist of the immune checkpoints PD-L1 and TIM3. CA-327 is currently undergoing IND-enabling studies, and the company expects to file an IND and initiate clinical testing of CA-327 in 2017.

11:20 Presentation to be Announced

11:50 Immunotherapy Potency Analysis Using Cellular Impedance

Brandon Lamarche, Ph.D., Research Scientist, ACEA Biosciences

The kinetics of cancer cell destruction by diverse immunotherapies (NK cells, T cells, CARTs, oncolytic viruses, checkpoint inhibitors, bispecific antibodies, BiTEs, combination therapies) can be monitored quantitatively, automatically, and in a label-free manner using the impedance-based xCELLigence instruments. Examples of using this technology to analyze potency and serial killing capacity, and to optimize constructs/conditions for treating both liquid and solid tumor targets will be provided.

We report potent costimulatory T-cell engagement of the immunoreceptor CD137 in a HER2-dependent manner, utilizing the CD137/HER2 bispecific PRS-343. In a humanized mouse model, PRS-343 displays dual activity based on monospecific HER2-targeting and bispecific, tumor-localized costimulation of CD137. Compared to known CD137-targeting antibodies in clinical development, this approach has the potential to provide a more localized activation of the immune system with higher efficacy and reduced peripheral toxicity.

I will discuss my investigation of how co-stimulation, with agonist anti-GITR, and checkpoint blockade, with antagonist anti-CTLA4 monoclonal antibodies, affect suppressive T cells in tumor microenvironment. In particular, I am involved in the study of the mechanisms of action responsible for the success or failure of these antibodies in preclinical mouse models.

The initiation and progression of cancer is controlled by both genetic and epigenetic events. Since epigenetic processes concurrently and concertedly regulate many cellular processes, their deregulation can contribute to a significant part of cancer hallmarks, including the capacity to avoid recognition and elimination by the immune system. Epigenetic drugs were shown to increase immunogenicity and recognizability of tumors by immune cells, and there is growing evidence that combination of epigenetic modulators with different cancer immunotherapies results in increased clinical benefit. Here, I will focus on the combination of epigenetic modulation with NK cell-based immunotherapies by demonstrating that HDAC inhibitor resminostat sensitizes tumor cells to NK cell attack and increases anti-tumoral NK cell response in vitro as well as in vivo.

4:35 Covalent Irreversible USP7 Inhibitors for Cancer Immunotherapy

Suresh Kumar, Ph.D., Director, R&D, Progenra, Inc.

Tumors employ diverse strategies to suppress and evade the immune system’s ability to recognize and destroy tumor cells. Presence of immune suppressive Foxp3+ regulatory T cells (Tregs) in the tumor microenvironment correlate with poor prognosis. Therefore, selective depletion of Tregs or impairment of Treg function is considered an attractive cancer immunotherapy approach. The deubiquitylase (DUB) USP7, a critical node in several cancer signaling pathways, is also essential for maintaining Treg functions. USP7 controls Treg function largely by regulating post-translational modification of Foxp3 and TIP60. Treg specific deletion of USP7 results in impairment of Treg functions and lethal autoimmunity in mice. Progenra has developed potent, selective covalent irreversible USP7 inhibitors that impair Treg functions ex vivo and in vivo. Most importantly, USP7 inhibitors exhibit powerful anti-tumor activity against variety of syngeneic solid tumor models in immunocompetent mice. In addition, Progenra’s USP7 inhibitors enhances the efficacy of anti-PD1 antibody and cancer vaccines. Along with the already established direct anti-tumor activities of USP7 inhibitors, these studies strongly suggest that USP7 inhibitors alone or in combination can improve the efficacy and expand the scope of cancer immunotherapy.

We have identified small molecule kinase inhibitors that act on myeloid cells infiltrating tumors. These compounds promote the tumor-specific local secretion of interferon gamma leading to activation of CD8+ and NK cells. Tumor specificity appears to be due to a reliance on tumor co-signalling for target pathways to be expressed. The agents have safety margins in the range of 15-30x and are effective in very low doses in mice in the order of 3 to 5 mg/kg/day. The compounds synergize both cytotoxic agents and checkpoint antibodies.

This session features various discussion groups that are led by a moderator/s who ensures focused conversations around the key issues listed. Attendees choose to join a specific group and the small, informal setting facilitates sharing of ideas and active networking. Continental breakfast is available for all participants.

Vaccination with HER2 peptide-pulsed DC1s stimulates a HER2 specific T-cell response. Anti-HER2 DC1 vaccination is a safe and immunogenic treatment to induce tumor-specific T-cell responses in HER2pos patients; immune and clinical responses were similar independent of vaccination route. The immune response in the sentinel lymph nodes, rather than in the peripheral blood, may serve as an endpoint more reflective of anti-tumor activity.

Therapeutic cancer vaccine development has suffered main failures over the years attributable to poor clinical trial design, poor patient selection, use of ineffective vaccines, and lack of agents to overcome resistance to T-cell-mediated tumor killing. The current landscape of immune-oncology offers the opportunity to overcome all of these factors. This talk will highlight opportunities in combinations with vaccines and one example selection of an ideal patient population based on a validated prognostic marker with mechanistic rationale for clinical evaluation of vaccine.

The protein Semaphorin 4D (SEMA4D) is highly expressed at the growing invasive margins of tumors, where it restricts the infiltration and migration of anti-tumor immune cells, such as antigen presenting cells and T lymphocytes, into the tumor microenvironment, indicating its role in promoting tumor growth. Antibody blockade reverses this effect, resulting in a shift in the immune balance and inhibition of tumor growth. Preclinical data supporting the combination of anti-semaphorin 4D (SEMA4D) with ipilimumab (anti-CTLA-4) or anti-PD-1/PD-L1 agents will be presented. The humanized IgG4 anti-SEMA4D was well tolerated in Phase I trials of patients with advanced refractory solid tumors, and Phase Ib/II studies of anti-SEMA4D in combination with immune checkpoint for the treatment of lung cancer and melanoma will be discussed.

10:15 Coffee Break in the Exhibit Hall with Poster Viewing

RADIOTHERAPY, CHEMOTHERAPY AND IMMUNOTHERAPY COMBINATIONS

11:00 Rational Development of Combinations of Antiangiogenic Therapy with Immune Checkpoint Blockers Using Mouse Models of HCC and Cirrhosis

Immunotherapies targeting the programmed death 1 (PD-1) co-inhibitory receptor have shown promise in hepatocellular carcinoma. One challenge will be incorporation of checkpoint blockade with existing, standard anti-angiogenic therapy. I will discuss several strategies addressing this important issue in liver cancer treatment using preclinical models.

The effect of immune checkpoint inhibitors in combination with other modalities on the tumor immune microenvironment is a key component to understand their mechanism of action and resistance. We are currently investigating the combination of anti-PD-1 antibodies and chemoradiation therapy (CRT) in patients with pancreatic and rectal cancer. Testing this combined modality in the neoadjuvant setting will allow us to study the safety of this approach and its effect on the tumor microenvironment by comparing TILs and other effectors and suppressor immune cells and receptors pre- and post-treatment. In addition, we will study the correlation between these immune biomarkers and clinical outcomes.